Ischemic heart disease is the most common cause of death among patients with diabetes. Maximizing the use of glucose by the heart under limited oxygen availability can be advantageous, since glucose is the most oxygen-efficient fuel, and this approach may be particularly advantageous in patients with diabetes. Glucagon-like peptide (GLP)-1 is a gut-derived peptide that improves glucose metabolism by actions in the pancreatic islets of Langerhans. Extrapancreatic actions of GLP-1 have also been described, including direct actions to augment myocardial glucose metabolism that are distinct from effects on systemic metabolism. Therefore it is possible that GLP-1 could be used therapeutically to modulate myocardial fuel selection, conferring benefits where preferential use of glucose fuel is advantageous. Data in support of this potential application includes in vitro, whole organ, whole animal and proof-of-principle human studies. One important barrier to the further evaluation of this approach in clinical trials is a lack of quantitative data in humans to guide dose selection for the use of GLP-1 as a modulator of myocardial fuel selection. Further, in type 2 diabetes GLP-1 resistance is recognized (i.e. actions on systemic metabolism are reduced compared to controls). Therefore GLP-1 effects in the heart may also differ between nondiabetic control and type 2 diabetic subjects. The objective of this proposal is to provide quantitative dose-response data in healthy control subjects and obese type 2 diabetic subjects, in support of the design of studies evaluating therapeutic applications of GLP-1 to heart disease. This will be accomplished using Positron Emission Tomography (PET), which allows quantitative measurement of multiple parameters of cardiac metabolism and is therefore an ideal tool for undertaking these measurements. We will study lean healthy non-diabetic subjects (Aim 1) and obese type 2 diabetic subjects (Aim 2). In each set of studies, four groups of 10 subjects will be studied during infusions of 0 (saline control), 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 (one study per subject). Cardiac metabolism will be measured using PET, using a dual- tracer approach which allows measurement of myocardial glucose uptake (the primary endpoint) along with total oxidation rate and myocardial perfusion (secondary endpoints). In concert with measures of circulating metabolites and regulatory hormones, we will produce the most comprehensive assessment of actions of GLP- 1 on myocardial metabolism in humans to date. Effects of each dose will be compared to the saline control, plus we will combine all data and use nonlinear curve-fitting to derive sensitivity (ED50) and maximal responses for GLP-1 effects on myocardial glucose uptake. Results from Aims 1 and 2 will be combined to allow direct comparison of the dose-response between nondiabetic control and type 2 diabetic subjects. PUBLIC HEALTH RELEVANCE: The proposed studies are necessary to quantify and better understand the effects of GLP-1 on myocardial metabolism in humans with and without type 2 diabetes. This will allow rational dose selection for further clinical studies evaluating the use of GLP-1 in the management of acute myocardial ischemia, which may be of particular benefit for people with diabetes